Inflammation

, Volume 40, Issue 3, pp 1062–1071

Elevated Galectin-9 Suppresses Th1 Effector Function and Induces Apoptosis of Activated CD4+T Cells in Osteoarthritis

ORIGINAL ARTICLE

Abstract

T cell immunoglobulin and mucin domain 3 (Tim-3) is a critical regulatory molecule found on activated Th1 cells, exhausted CD8+ T cells, and resting monocytes/macrophages. Galectin-9 (Gal-9) is an identified ligand for Tim-3. Interaction between Tim-3 and Gal-9 is thought to inhibit Th1 responses. The regulation and function of Tim-3 and Gal-9 in osteoarthritis (OA) have not been intensively investigated. We found that in peripheral blood, CD4+ T cells, but not CD8+ T cells or CD14+ monocytes, from OA patients presented significantly elevated Tim-3 and Gal-9 expression compared to those from healthy controls (HC). The CD4+ T cells from OA did not present altered Th1, Th2, and Th17 composition in the peripheral blood, but secreted less Th1 cytokine interleukin 2 (IL-2) and interferon gamma (IFN-γ) after activation. Further investigation demonstrated that Gal-9 induced high levels of apoptosis in activated CD4+ T cells from OA patients. Inhibition of Gal-9 resulted in significantly higher IL-2 and IFN-γ expression that was directly correlated with the number of non-apoptotic cells. In the synovial fluid, both secreted Gal-9 and surface Gal-9 levels were significantly higher in less-severe grade 2 OA patients than in more-severe grade 4 OA patients. Surface Tim-3 was also higher in synovial fluid CD8+ T cells and CD14+ monocytes from grade 2 OA patients and lower in grade 4 OA patients. Together, these results suggested that Tim-3 and Gal-9 could downregulate T cell inflammation in OA, and could be utilized as a novel therapeutic strategy.

KEY WORDS

galectin-9 osteoarthritis Tim-3 

References

  1. 1.
    Monney, L., C.A. Sabatos, J.L. Gaglia, A. Ryu, H. Waldner, T. Chernova, S. Manning, et al. 2002. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415 (6871): 536–541. doi:10.1038/415536a.CrossRefPubMedGoogle Scholar
  2. 2.
    Anderson, A.C. 2012. Tim-3, a negative regulator of anti-tumor immunity. Current Opinion in Immunology 24 (2): 213–216. doi:10.1016/j.coi.2011.12.005.CrossRefPubMedGoogle Scholar
  3. 3.
    McMahan, R.H., L. Golden-Mason, M.I. Nishimura, B.J. McMahon, M. Kemper, T.M. Allen, D.R. Gretch, and H.R. Rosen. 2010. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. The Journal of Clinical Investigation 120 (12): 4546–4557. doi:10.1172/jci43127.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lhuillier, C., C. Barjon, T. Niki, A. Gelin, F. Praz, O. Morales, S. Souquere, et al. 2015. Impact of exogenous galectin-9 on human T cells: CONTRIBUTION OF THE T CELL RECEPTOR COMPLEX TO ANTIGEN-INDEPENDENT ACTIVATION BUT NOT TO APOPTOSIS INDUCTION. The Journal of Biological Chemistry 290 (27): 16797–16811. doi:10.1074/jbc.M115.661272.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Oomizu, S., T. Arikawa, T. Niki, T. Kadowaki, M. Ueno, N. Nishi, A. Yamauchi, T. Hattori, T. Masaki, and M. Hirashima. 2012. Cell surface galectin-9 expressing Th cells regulate Th17 and Foxp3+ Treg development by galectin-9 secretion. PloS One 7 (11): e48574. doi:10.1371/journal.pone.0048574.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhu, C., A.C. Anderson, A. Schubart, H. Xiong, J. Imitola, S.J. Khoury, X.X. Zheng, T.B. Strom, and V.K. Kuchroo. 2005. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nature Immunology 6 (12): 1245–1252. doi:10.1038/ni1271.CrossRefPubMedGoogle Scholar
  7. 7.
    Sabatos, C.A., S. Chakravarti, E. Cha, A. Schubart, A. Sanchez-Fueyo, X.X. Zheng, A.J. Coyle, T.B. Strom, G.J. Freeman, and V.K. Kuchroo. 2003. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nature Immunology 4 (11): 1102–1110. doi:10.1038/ni988.CrossRefPubMedGoogle Scholar
  8. 8.
    Jones, R.B., L.C. Ndhlovu, J.D. Barbour, P.M. Sheth, A.R. Jha, B.R. Long, J.C. Wong, et al. 2008. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. The Journal of Experimental Medicine 205 (12): 2763–2779. doi:10.1084/jem.20081398.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    de Lange-Brokaar, B.J., A. Ioan-Facsinay, G.J. van Osch, A.M. Zuurmond, J. Schoones, R.E. Toes, T.W. Huizinga, and M. Kloppenburg. 2012. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis and Cartilage 20 (12): 1484–1499.CrossRefPubMedGoogle Scholar
  10. 10.
    Ishii, H., H. Tanaka, K. Katoh, H. Nakamura, M. Nagashima, and S. Yoshino. 2002. Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis. Osteoarthritis and Cartilage 10 (4): 277–281. doi:10.1053/joca.2001.0509.CrossRefPubMedGoogle Scholar
  11. 11.
    Sakkas, L.I., and C.D. Platsoucas. 2007. The role of T cells in the pathogenesis of osteoarthritis. Arthritis and Rheumatism 56 (2): 409–424. doi:10.1002/art.22369.CrossRefPubMedGoogle Scholar
  12. 12.
    Seki, M., K.M. Sakata, S. Oomizu, T. Arikawa, A. Sakata, M. Ueno, A. Nobumoto, et al. 2007. Beneficial effect of galectin 9 on rheumatoid arthritis by induction of apoptosis of synovial fibroblasts. Arthritis and Rheumatism 56 (12): 3968–3976. doi:10.1002/art.23076.CrossRefPubMedGoogle Scholar
  13. 13.
    Liu, Y., Q. Shu, L. Gao, N. Hou, D. Zhao, X. Liu, X. Zhang, et al. 2010. Increased Tim-3 expression on peripheral lymphocytes from patients with rheumatoid arthritis negatively correlates with disease activity. Clinical Immunology 137 (2): 288–295. doi:10.1016/j.clim.2010.07.012.CrossRefPubMedGoogle Scholar
  14. 14.
    Chen, J., G. Sun, F. Chen, Y. Fang, M.H. Gates, and S. Yang. 2015. T-cell immunoglobulin domain and mucin domain 3 polymorphism affects cytokine expression in different cells and is associated with increased susceptibility to knee osteoarthritis. Gene 566 (1): 32–36. doi:10.1016/j.gene.2015.04.024.CrossRefPubMedGoogle Scholar
  15. 15.
    Li, S., Y. Ren, D. Peng, Z. Yuan, S. Shan, H. Sun, X. Yan, H. Xiao, G. Li, and H. Song. 2015. TIM-3 genetic variations affect susceptibility to osteoarthritis by interfering with interferon gamma in CD4+ T cells. Inflammation 38 (5): 1857–1863. doi:10.1007/s10753-015-0164-7.CrossRefPubMedGoogle Scholar
  16. 16.
    Altman, R., E. Asch, D. Bloch, G. Bole, D. Borenstein, K. Brandt, W. Christy, et al. 1986. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria Committee of the American Rheumatism Association. Arthritis and Rheumatism 29 (8): 1039–1049.CrossRefPubMedGoogle Scholar
  17. 17.
    Demehri, S., A. Guermazi, and C.K. Kwoh. 2016. Diagnosis and longitudinal assessment of osteoarthritis: review of available imaging techniques. Rheumatic Diseases Clinics of North America 42 (4): 607–620. doi:10.1016/j.rdc.2016.07.004.CrossRefPubMedGoogle Scholar
  18. 18.
    Groom, J.R., and A.D. Luster. 2011. CXCR3 in T cell function. Experimental Cell Research 317 (5): 620–631. doi:10.1016/j.yexcr.2010.12.017.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cosmi, L., F. Annunziato, M.I.G. Galli, R.M.E. Maggi, K. Nagata, and S. Romagnani. 2000. CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease. European Journal of Immunology 30 (10): 2972–2979.CrossRefPubMedGoogle Scholar
  20. 20.
    Acosta-Rodriguez, E.V., L. Rivino, J. Geginat, D. Jarrossay, M. Gattorno, A. Lanzavecchia, F. Sallusto, and G. Napolitani. 2007. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nature Immunology 8 (6): 639–646. doi:10.1038/ni1467.CrossRefPubMedGoogle Scholar
  21. 21.
    Sakuishi, K., L. Apetoh, J.M. Sullivan, B.R. Blazar, V.K. Kuchroo, and A.C. Anderson. 2010. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. The Journal of Experimental Medicine 207 (10): 2187–2194. doi:10.1084/jem.20100643.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hsieh, J.L., A.L. Shiau, C.H. Lee, S.J. Yang, B.O. Lee, I.M. Jou, C.L. Wu, S.H. Chen, and P.C. Shen. 2013. CD8+ T cell-induced expression of tissue inhibitor of metalloproteinses-1 exacerbated osteoarthritis. International Journal of Molecular Sciences 14 (10): 19951–19970. doi:10.3390/ijms141019951.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Scanzello, C.R., B. McKeon, B.H. Swaim, E. DiCarlo, E.U. Asomugha, V. Kanda, A. Nair, et al. 2011. Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular characterization and relationship to symptoms. Arthritis and Rheumatism 63 (2): 391–400. doi:10.1002/art.30137.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Benito, M.J., D.J. Veale, O. FitzGerald, W.B. van den Berg, and B. Bresnihan. 2005. Synovial tissue inflammation in early and late osteoarthritis. Annals of the Rheumatic Diseases 64 (9): 1263–1267. doi:10.1136/ard.2004.025270.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ponchel, F., A.N. Burska, E.M. Hensor, R. Raja, M. Campbell, P. Emery, and P.G. Conaghan. 2015. Changes in peripheral blood immune cell composition in osteoarthritis. Osteoarthritis and Cartilage 23 (11): 1870–1878. doi:10.1016/j.joca.2015.06.018.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Moradi, B., N. Rosshirt, E. Tripel, J. Kirsch, A. Barie, F. Zeifang, T. Gotterbarm, and S. Hagmann. 2015. Unicompartmental and bicompartmental knee osteoarthritis show different patterns of mononuclear cell infiltration and cytokine release in the affected joints. Clinical and Experimental Immunology 180 (1): 143–154. doi:10.1111/cei.12486.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ohshima, S., S. Kuchen, C.A. Seemayer, D. Kyburz, A. Hirt, S. Klinzing, B.A. Michel, et al. 2003. Galectin 3 and its binding protein in rheumatoid arthritis. Arthritis and Rheumatism 48 (10): 2788–2795. doi:10.1002/art.11287.CrossRefPubMedGoogle Scholar
  28. 28.
    Guevremont, M., J. Martel-Pelletier, C. Boileau, F.T. Liu, M. Richard, J.C. Fernandes, J.P. Pelletier, and P. Reboul. 2004. Galectin-3 surface expression on human adult chondrocytes: a potential substrate for collagenase-3. Annals of the Rheumatic Diseases 63 (6): 636–643. doi:10.1136/ard.2003.007229.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Reboul, P., J. Martel-Pelletier, and J.P. Pelletier. 2004. Galectin-3 in osteoarthritis: when the fountain of youth doesn’t deliver its promises. Current Opinion in Rheumatology 16 (5): 595–598.CrossRefPubMedGoogle Scholar
  30. 30.
    Toegel, S., D. Weinmann, S. Andre, S.M. Walzer, M. Bilban, S. Schmidt, C. Chiari, et al. 2016. Galectin-1 couples glycobiology to inflammation in osteoarthritis through the activation of an NF-kappaB-regulated gene network. Journal of Immunology 196 (4): 1910–1921. doi:10.4049/jimmunol.1501165.CrossRefGoogle Scholar
  31. 31.
    Zhang, Y., C.J. Ma, J.M. Wang, X.J. Ji, X.Y. Wu, Z.S. Jia, J.P. Moorman, and Z.Q. Yao. 2011. Tim-3 negatively regulates IL-12 expression by monocytes in HCV infection. PloS One 6 (5): e19664. doi:10.1371/journal.pone.0019664.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Zhang, Y., C.J. Ma, J.M. Wang, X.J. Ji, X.Y. Wu, J.P. Moorman, and Z.Q. Yao. 2012. Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes. Journal of Leukocyte Biology 91 (2): 189–196. doi:10.1189/jlb.1010591.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    DeKruyff, R.H., X. Bu, A. Ballesteros, C. Santiago, Y.L. Chim, H.H. Lee, P. Karisola, et al. 2010. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. Journal of Immunology 184 (4): 1918–1930. doi:10.4049/jimmunol.0903059.CrossRefGoogle Scholar
  34. 34.
    Sada-Ovalle, I., L. Chavez-Galan, L. Torre-Bouscoulet, L. Nava-Gamino, L. Barrera, P. Jayaraman, M. Torres-Rojas, M.A. Salazar-Lezama, and S.M. Behar. 2012. The Tim3-galectin 9 pathway induces antibacterial activity in human macrophages infected with Mycobacterium tuberculosis. Journal of Immunology 189 (12): 5896–5902. doi:10.4049/jimmunol.1200990.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of OrthopedicsBayi Hospital Affiliated Nanjing University of Chinese MedicineNanjingPeople’s Republic of China
  2. 2.Department of OrthopedicsXiamen University Affiliated Chenggong HospitalXiamenPeople’s Republic of China
  3. 3.Department of Outpatient, Jinling HospitalNanjing University School of MedicineNanjingPeople’s Republic of China

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